Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

• the present bis-aza-bicyclic compounds generally show minimal in vivo stimulation of dopaminergic systems, reflective of reduced or minimal neurological side effects in the clinical use of these compounds.
• the present invention is directed to the use of certain bis-aza-bicyclic compounds, vii., racemic or optically active compounds of the formula ##STR2## and the pharmaceutically acceptable acid addition salts thereof, wherein X is N or CH;
• Y is ##STR3##
• Z is ##STR4## SCH 2 , OCH 2 , --Y 1 (CH 2 ) n or Y 1 (CH 2 ) n substituted on carbon with up to 2 methyl groups;
• n 1 or 2;
• y 1 is CH 2 , NH or NCH 3 ;
• a particularly preferred compound is that wherein Z is Y 1 (CH 2 ) n , Y 1 is CH 2 , n is 1 and X is N.
• Said pharmaceutically acceptable acid addition salts include but are not limited to those with HCl, HNO 3 , H 2 SO 4 , H 3 PO 4 , pCH 3 C 6 H 4 SO 3 H or HOOCCH 2 CH 2 COOH. These salts are prepared by conventional methods, for example, by combining molar equivalent amounts of a compound of the formula (I) and the appropriate acid in a solvent from which the desired salt is of low solubility and precipitates directly, or from which the salt can be isolated by concentration or addition of a non-solvent.
• the present invention also encompasses pharmaceutical compositions comprising an amount of a compound of the formula (I) which is effective in the treatment of substance abuse or addiction.
• the compounds of the above formula (I) are readily prepared by a number of methods.
• One general method which is the preferred method for all racemic compounds and the preferred method for optically active compounds when Y is other than an imido group, is to displace the sulfonate ester group of a racemic or optically active compound of the formula ##STR6## with an anion Y - , wherein R, X and Y are as defined above, and Y - represents the anion of a salt MY where M is most simply an alkali metal such as sodium.
• the required salt When the required salt is not available commercially, as is most frequently the case, it is convenient to form the required salt in situ in the form of the sodium salt, e.g., irreversibly by the action of sodium hydride on the compound of the formula Y--H; or reversibly by reaction with a base such as Na 2 CO 3 which is not itself nucleophilic.
• This process is representative of such displacement reactions in general. It is generally carried out in a reaction inert-solvent, preferably one which is aprotic and certainly one which is less acidic than the compound Y--H.
• Particularly useful solvents in the present instance are acetonitrile and dimethylformamide.
• Temperature is not generally critical in this process, but, in order to achieve complete conversion within a reasonably short period of time, elevated temperatures, e.g., 90°-120° C., are generally preferred. Also for the purpose of forcing this second order displacement reaction to completion within a reasonable period of time, a molar excess of one of the reactants, usually the more readily available salt, MY, is generally employed in this process. Methyl is the preferred value of R in this process, for ease of preparation of the mesylate ester and for the facile displacement of the mesylate anion.
• the product is isolated by conventional methods of concentration, evaporation, extraction, chromatography and crystallization, with, if direct formation of an acid addition salt is desired, addition of an appropriate acid in an appropriate amount, e.g., addition of one molar equivalent of HCl if the mono-hydrochloride salt is desired.
• reaction-inert solvent refers to a solvent which does not interact with reactants, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
• the compounds of the formula (I) wherein the group Y is an imido group are also generally prepared from the corresponding amine of the formula ##STR8## by the action of an anhydride of the formula ##STR9## wherein X and Z are as defined above.
• the amine (VI) and the anhydride (VII) generally in about molar equivalents, are heated to about 100°-160° C. in a reaction inert solvent. Particularly well suited as solvent here are mixed xylenes boiling in the range of about 138°-142° C. The reaction is then conveniently carried out at the reflux temperature of said mixed xylenes.
• a compound of the formula (I), or a pharmaceutically-acceptable salt thereof is administered in an amount of about 2-200 mg/day, in single or divided daily doses. In particular cases, dosages outside that range are prescribed at the discretion of the attending physician.
• the preferred route of administration is generally oral, but parenteral administration (e.g., intramuscular, intravenous, intradermal) will be preferred in special cases, e.g., where oral absorption is impaired as by disease, or the patient is unable to swallow.
• compositions comprising at least one of the compounds of the formula (I), or a salt thereof, together with a pharmaceutically acceptable vehicle or diluent.
• Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; and, for parenteral administration, in the form of injectable solutions or suspensions, and the like.
• the reaction was refluxed for 18 hours; and then concentrated in vacuo to an oil.
• the oil was dissolved in methylene chloride/water mixture (35 ml of each).
• the pH of the well-stirred mixture was then adjusted to 2 with 6N HCl , and the phases were then separated.
• the organic phase was combined with 10 ml of water, and the pH of the mixture likewise adjusted to 2.
• the two acidic aqueous extracts were combined and stirred with an equal volume of methylene chloride while the pH was adjusted to 10 with saturated Na 2 CO 3 .
• the phases were separated and the aqueous phase was extracted twice with fresh 50 ml portions of methylene chloride.
• the three organic extracts were combined, treated with activated carbon, dried (Na 2 SO 4 ) and stripped to an oil which was crystallized from isopropanol to yield 31 mg (9.5%) of present title product identical with that of Method A.
• the combined acidic extracts were stirred with methylene chloride (40 ml) with the pH adjusted to 10.0 (saturated Na 2 CO 3 ).
• the phases were separated, and the aqueous phase was extracted twice with fresh 40 ml portions of methylene chloride.
• the basic organic extracts were combined, treated with activated carbon, dried (Na 2 SO 4 ) and concentrated in vacuo to a solid which was crystallized from 7 ml of isopropanol to yield 164 mg (83%) of the title compound as colorless crystals, identical with the products of methods A and B.
• meso-3,4-Dimethylsuccinimido (50%); crystallized from CH 2 Cl 2 :isopropanol; mp 141°-142° C.; TLC Rf 0.56.
• 1,2,4-Triazol-1-yl (62.3%); crystallized from ethyl acetate:hexane; mp 150°-152° C.; TLC Rf 0.37; HRMS 299.1853, calcd. 299.1858.
• Tetrazol-2-yl (30.5%); amorphous; TLC Rf 0.64; HRMS 300.1792, calcd. 300.1809.
• Succinimido (36.3%); crystallized from CH 2 Cl 2 :ether; mp 164°-165° C.; TLC Rf 0.41; HRMS 328.1880, calcd. 328.1899.
• 1,2,4-Triazol-1-yl (18.7%); crystallized from isopropyl ether:hexane; mp 109°-110° C.; HRMS 298.1943, calcd. 298.1906; TLC Rf 0.37.
• Piperidine-2,6-dion-1-yl (22.8%); crystallized from CH 2 Cl 2 : isopropyl ether; mp 114°-115° C.; TLC Rf 0.44; HRMS 342.2043, calcd. 342.2055.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Addiction (AREA)
• Psychiatry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1990
  • 1990-06-29 WO PCT/US1990/003708 patent/WO1992000075A1/fr not_active Ceased
• 1991
  • 1991-05-28 DE DE69106516T patent/DE69106516T2/de not_active Expired - Fee Related
  • 1991-05-28 HU HU924138D patent/HUT62797A/hu unknown
  • 1991-05-28 EP EP91910566A patent/EP0536173B1/fr not_active Expired - Lifetime
  • 1991-05-28 DK DK91910566.8T patent/DK0536173T3/da active
  • 1991-05-28 AT AT91910566T patent/ATE116545T1/de not_active IP Right Cessation
  • 1991-05-28 AU AU79094/91A patent/AU651977B2/en not_active Ceased
  • 1991-05-28 CA CA002086335A patent/CA2086335C/fr not_active Expired - Fee Related
  • 1991-05-28 ES ES91910566T patent/ES2066447T3/es not_active Expired - Lifetime
  • 1991-05-28 WO PCT/US1991/003749 patent/WO1992000074A2/fr not_active Ceased
  • 1991-05-28 JP JP91510300A patent/JPH05507274A/ja active Pending
  • 1991-06-23 IL IL9858891A patent/IL98588A/en not_active IP Right Cessation
  • 1991-06-27 NZ NZ238750A patent/NZ238750A/xx not_active IP Right Cessation
  • 1991-06-28 MY MYPI91001174A patent/MY106553A/en unknown
  • 1991-06-28 ZA ZA915012A patent/ZA915012B/xx unknown
  • 1991-06-28 IE IE225991A patent/IE64467B1/en not_active IP Right Cessation
• 1992
  • 1992-12-28 KR KR1019920703374A patent/KR930701171A/ko not_active Ceased
• 1995
  • 1995-01-25 US US08/377,874 patent/US5616585A/en not_active Expired - Fee Related

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